Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

J Invest Dermatol. 2019 Jul;139(7):1449-1458.e1. doi: 10.1016/j.jid.2019.01.008. Epub 2019 Jan 23.

Abstract

Cutaneous squamous cell carcinoma from the head and neck typically metastasize to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland squamous cell carcinoma. UV radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cutaneous squamous cell carcinoma. In this study, we used whole genome sequencing data from 15 cutaneous squamous cell carcinoma metastases and show that a UV mutation signature is pervasive across the cohort and distinct from mucosal squamous cell carcinoma. The mutational burden was exceptionally high and concentrated in some regions of the genome, especially insulator elements (mean 162 mutations/megabase). We therefore evaluated the likely impact of UV-induced mutations on the dipyrimidine-rich binding site of the main human insulator protein, CCCTC-binding factor, and the possible implications on CCCTC-binding factor function and the spatial organization of the genome. Our findings suggest that mutation signature analysis may be useful in determining the origin of metastases in the neck and the parotid gland. Furthermore, UV-induced DNA damage to insulator binding sites may play a role in the carcinogenesis and progression of cutaneous squamous cell carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • CCCTC-Binding Factor / genetics*
  • Carcinoma, Squamous Cell / diagnosis
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / secondary
  • Cohort Studies
  • DNA Mutational Analysis
  • Female
  • Humans
  • Lymphatic Metastasis / diagnosis
  • Lymphatic Metastasis / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Metastasis
  • Parotid Neoplasms / diagnosis
  • Parotid Neoplasms / genetics*
  • Parotid Neoplasms / secondary
  • Skin Neoplasms / diagnosis
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Ultraviolet Rays / adverse effects
  • Whole Genome Sequencing

Substances

  • CCCTC-Binding Factor